Design, synthesis and biological evaluation of new RNF126-based p300/CBP degraders.

Histone acetyltransferase CREB-binding protein (CBP) and its homologous protein p300 are key transcriptional activators that can activate oncogene transcription, which present promising targets for cancer therapy. Here, we designed and synthesized a series of p300/CBP targeted low molecular weight PROTACs by assembling the covalent ligand of RNF126 E3 ubiquitin ligase and the bromodomain ligand of the p300/CBP. The optimal molecule A8 could effectively degrade p300 and CBP through the ubiquitin-proteasome system in time- and concentration-dependent manners, with half-maximal degradation (DC50) concentrations of 208.35/454.35 nM and 82.24/79.45 nM for p300/CBP in MV4-11 and Molm13 cell lines after 72 h of treatment. And the degradation of p300/CBP by A8 is dependent on the ubiquitin-proteasome pathway and its simultaneous interactions with the target proteins and RNF126. A8 exhibits good antiproliferative activity in a series of p300/CBP-dependent cancer cells. It could transcriptionally inhibit the expression of c-Myc, induce cell cycle arrest in the G0/G1 phase and apoptosis in MV4-11 cells. This study thus provided us a new chemotype for the development of drug-like PROTACs targeting p300/CBP, which is expected to be applied in cancer therapy.

Age-related differences in auditory spatial processing revealed by acoustic change complex.

Objectives: The auditory spatial processing abilities mature throughout childhood and degenerate in older adults. This study aimed to compare the differences in onset cortical auditory evoked potentials (CAEPs) and location-evoked acoustic change complex (ACC) responses among children, adults, and the elderly and to investigate the impact of aging and development on ACC responses. Design: One hundred and seventeen people were recruited in the study, including 57 typically-developed children, 30 adults, and 30 elderlies. The onset-CAEP evoked by white noise and ACC by sequential changes in azimuths were recorded. Latencies and amplitudes as a function of azimuths were analyzed using the analysis of variance, Pearson correlation analysis, and multiple linear regression model. Results: The ACC N1'-P2' amplitudes and latencies in adults, P1'-N1' amplitudes in children, and N1' amplitudes and latencies in the elderly were correlated with angles of shifts. The N1'-P2' and P2' amplitudes decreased in the elderly compared to adults. In Children, the ACC P1'-N1' responses gradually differentiated into the P1'-N1'-P2' complex. Multiple regression analysis showed that N1'-P2' amplitudes (R2 = 0.33) and P2' latencies (R2 = 0.18) were the two most variable predictors in adults, while in the elderly, N1' latencies (R2 = 0.26) explained most variances. Although the amplitudes of onset-CAEP differed at some angles, it could not predict angle changes as effectively as ACC responses. Conclusion: The location-evoked ACC responses varied among children, adults, and the elderly. The N1'-P2' amplitudes and P2' latencies in adults and N1' latencies in the elderly explained most variances of changes in spatial position. The differentiation of the N1' waveform was observed in children. Further research should be conducted across all age groups, along with behavioral assessments, to confirm the relationship between aging and immaturity in objective ACC responses and poorer subjective spatial performance. Significance: ACCs evoked by location changes were assessed in adults, children, and the elderly to explore the impact of aging and development on these differences.

Neutron Activation Analysis Based on AB-BNCT Treatment Room.

ABSTRACT: Boron neutron capture therapy (BNCT) is an ideal binary targeted radiotherapy for treating refractory tumors. An accelerator-based BNCT (AB-BNCT) neutron source has attracted more and more attention due to its advantages such as higher neutron yield in the keV energy region, less gamma radiation, and higher safety. In addition to 10B, neutrons also react with other elements in the treatment room during BNCT to produce many activation products. Due to the long half-life of some activation products, there will be residual radiation after the end of treatment and the shutdown of the accelerator, which has adverse effects on radiation workers. Therefore, the ambient dose equivalent rate in the treatment room needs to be evaluated. The AB-BNCT neutron source model proposed by Li is studied in this paper. Based on the Monte Carlo method, the Geant4 platform was used to simulate the dose induced by radionuclides near the Beam Shaping Assembly (BSA) of the source. It is concluded that the concrete wall contributed the most to the radiation dose. The dose rate of 2.45 µSv h-1 after 13 min of shutdown meets the dose rate limit of 2.5 µSv h-1, at which point it is safe for workers to enter the treatment room area.

Case Report: Antibiotic Irrigation and Drainage Tube for Managing Chronic Suppurative Otitis Media After Cochlear Implantation.

Cochlear implantation (CI) is the most effective solution for patients with severe-to-profound sensorineural hearing loss, especially in children. However, a major postoperative complication, known as chronic suppurative otitis media (CSOM), poses challenges for both doctors and families of the patients, which can affect post-CI hearing outcomes. We present the case of post-CI CSOM in a 15-year-old girl. She had been utilizing a unilateral cochlear implant for 7 years and had been experiencing intermittent earache and discharge in her only audible ear for the past 15 months. After antibiotic treatment failed to resolve her symptoms, we opted for a tympanomastoidectomy, and removed the receiver-stimulator package while keeping the electrode inside her cochlea. Simultaneously, we inserted an irrigation and drainage tube into the mastoid and middle ear space to discharge the exudate and control infection by applying topical antibiotics. The patient's ear discharge had resolved within 1 month, and her tympanic membrane healed naturally. Our successful experience shows that antibiotic irrigation and draining have effectively controlled infection and accelerated wound healing in this patient with post-CI CSOM, and it further prompted the patient to undergo bilateral CI 9 months later.

Parvalbumin and Somatostatin: Biomarkers for Two Parallel Tectothalamic Pathways in the Auditory Midbrain.

The inferior colliculus (IC) represents a crucial relay station in the auditory pathway, located in the midbrain's tectum and primarily projecting to the thalamus. Despite the identification of distinct cell classes based on various biomarkers in the IC, their specific contributions to the organization of auditory tectothalamic pathways have remained poorly understood. In this study, we demonstrate that IC neurons expressing parvalbumin (ICPV+) or somatostatin (ICSOM+) represent two minimally overlapping cell classes throughout the three IC subdivisions in mice of both sexes. Strikingly, regardless of their location within the IC, these neurons predominantly project to the primary and secondary auditory thalamic nuclei, respectively. Cell class-specific input tracing suggested that ICPV+ neurons primarily receive auditory inputs, whereas ICSOM+ neurons receive significantly more inputs from the periaqueductal gray and the superior colliculus (SC), which are sensorimotor regions critically involved in innate behaviors. Furthermore, ICPV+ neurons exhibit significant heterogeneity in both intrinsic electrophysiological properties and presynaptic terminal size compared with ICSOM+ neurons. Notably, approximately one-quarter of ICPV+ neurons are inhibitory neurons, whereas all ICSOM+ neurons are excitatory neurons. Collectively, our findings suggest that parvalbumin and somatostatin expression in the IC can serve as biomarkers for two functionally distinct, parallel tectothalamic pathways. This discovery suggests an alternative way to define tectothalamic pathways and highlights the potential usefulness of Cre mice in understanding the multifaceted roles of the IC at the circuit level.

Unleashing the Potential of Camptothecin: Exploring Innovative Strategies for Structural Modification and Therapeutic Advancements.

Camptothecin (CPT) is a potent anti-cancer agent targeting topoisomerase I (TOP1). However, CPT has poor pharmacokinetic properties, causes toxicities, and leads to drug resistance, which limit its clinical use. In this paper, to review the current state of CPT research. We first briefly explain CPT's TOP1 inhibition mechanism and the key hurdles in CPT drug development. Then we examine strategies to overcome CPT's limitations through structural modifications and advanced delivery systems. Though modifications alone seem insufficient to fully enhance CPT's therapeutic potential, structure-activity relationship analysis provides insights to guide optimization of CPT analogs. In comparison, advanced delivery systems integrating controlled release, imaging capabilities, and combination therapies via stimulus-responsive linkers and targeting moieties show great promise for improving CPT's pharmacological profile. Looking forward, multifaceted approaches combining selective CPT derivatives with advanced delivery systems, informed by emerging biological insights, hold promise for fully unleashing CPT's anti-cancer potential.

Pharmacological inhibition of EZH2 using a covalent inhibitor suppresses human ovarian cancer cell migration and invasion.

Metastasis is the cause of poor prognosis in ovarian cancer (OC). Enhancer of Zeste homolog 2 (EZH2), a histone-lysine N-methyltransferase enzyme, promotes OC cell migration and invasion by regulating the expression of tissue inhibitor of metalloproteinase-2 (TIMP2) and matrix metalloproteinases-9 (MMP9). Hence, we speculated that EZH2-targeting therapy might suppress OC migration and invasion. In this study, the expression of EZH2, TIMP2, and MMP9 in OC tissues and cell lines was analyzed using The Cancer Genome Atlas (TCGA) database and western blotting, respectively. The effects of SKLB-03220, an EZH2 covalent inhibitor, on OC cell migration and invasion were investigated using wound-healing assays, Transwell assays, and immunohistochemistry. TCGA database analysis confirmed that the EZH2 and MMP9 mRNA expression was significantly higher in OC tissues, whereas TIMP2 expression was significantly lower than that in normal ovarian tissues. Moreover, EZH2 negatively correlated with TIMP2 and positively correlated with MMP9 expression. In addition to the anti-tumor activity of SKLB-03220 in a PA-1 xenograft model, immunohistochemistry results showed that SKLB-03220 markedly increased the expression of TIMP2 and decreased the expression of MMP9. Additionally, wound-healing and Transwell assays showed that SKLB-03220 significantly inhibited the migration and invasion of both A2780 and PA-1 cells in a concentration-dependent manner. SKLB-03220 inhibited H3K27me3 and MMP9 expression and increased TIMP2 expression in PA-1 cells. Taken together, these results indicate that the EZH2 covalent inhibitor SKLB-03220 inhibits metastasis of OC cells by upregulating TIMP2 and downregulating MMP9, and could thus serve as a therapeutic agent for OC.

Design and synthesis of the first PARP-1 and proteasome dual inhibitors to treat breast cancer.

PARP-1 is a crucial factor in repairing DNA single strand damage and maintaining genomic stability. However, the use of PARP-1 inhibitors is limited to combination with chemotherapy or radiotherapy, or as a single agent for indications carrying HRR defects. The ubiquitin-proteasome system processes the majority of cellular proteins and is the principal manner by which cells regulate protein homeostasis. Proteasome inhibitors can cooperate with PARP-1 inhibitors to inhibit DNA homologous recombination repair function. In this study, we designed and synthesized the first dual PARP-1 and proteasome inhibitor based on Olaparib and Ixazomib. Both compounds 42d and 42i exhibited excellent proliferation inhibition and dual-target synergistic effects on cells that were insensitive to PARP-1 inhibitors. Further mechanistic evaluations revealed that 42d and 42i could inhibit homologous recombination repair function by down-regulating the expression of BRCA1 and RAD51. Additionally, 42i induced more significant apoptosis and showed better inhibitory effect on cell proliferation in clonal formation experiments in breast cancer cells than 42d. In summary, our study presented a new class of dual PARP-1/proteasome inhibitors with significant synergistic effects for the treatment of breast cancer.

Enhanced YOLOv5 network-based object detection (BALFilter Reader) promotes PERFECT filter-enabled liquid biopsy of lung cancer from bronchoalveolar lavage fluid (BALF).

Liquid biopsy of cancers, detecting tumor-related information from liquid samples, has attracted wide attentions as an emerging technology. Our previously reported large-area PERFECT (Precise-Efficient-Robust-Flexible-Easy-Controllable-Thin) filter has demonstrated competitive sensitivity in recovering rare tumor cells from clinical samples. However, it is time-consuming and easily biased to manually inspect rare target cells among numerous background cells distributed in a large area (Φ ≥ 13 mm). This puts forward an urgent demand for rapid and bias-free inspection. Hereby, this paper implemented deep learning-based object detection for the inspection of rare tumor cells from large-field images of PERFECT filters with hematoxylin-eosin (HE)-stained cells recovered from bronchoalveolar lavage fluid (BALF). CenterNet, EfficientDet, and YOLOv5 were trained and validated with 240 and 60 image blocks containing tumor and/or background cells, respectively. YOLOv5 was selected as the basic network given the highest mAP@0.5 of 92.1%, compared to those of CenterNet and EfficientDet at 85.2% and 91.6%, respectively. Then, tricks including CIoU loss, image flip, mosaic, HSV augmentation and TTA were applied to enhance the performance of the YOLOv5 network, improving mAP@0.5 to 96.2%. This enhanced YOLOv5 network-based object detection, named as BALFilter Reader, was tested and cross-validated on 24 clinical cases. The overall diagnosis performance (~2 min) with sensitivity@66.7% ± 16.7%, specificity@100.0% ± 0.0% and accuracy@75.0% ± 12.5% was superior to that from two experienced pathologists (10-30 min) with sensitivity@61.1%, specificity@16.7% and accuracy@50.0%, with the histopathological result as the gold standard. The AUC of the BALFilter Reader is 0.84 ± 0.08. Moreover, a customized Web was developed for a user-friendly interface and the promotion of wide applications. The current results revealed that the developed BALFilter Reader is a rapid, bias-free and easily accessible AI-enabled tool to promote the transplantation of the BALFilter technique. This work can easily expand to other cytopathological diagnoses and improve the application value of micro/nanotechnology-based liquid biopsy in the era of intelligent pathology.

Design, synthesis and biological evaluation of indazole derivatives as selective covalent inhibitors of FGFR4 in wild-type and gatekeeper mutants.

Fibroblast growth factor receptor 4 (FGFR4) has been proved to be an effective target for cancer therapy. Aberration in FGF19/FGFR4 signaling is oncogenic driving force in human hepatocellular carcinoma (HCC). FGFR4 gatekeeper mutations induced acquired resistance remains an unmet clinical challenge for HCC treatment. In this study, a series of 1H-indazole derivatives were designed and synthesized as new irreversible inhibitors of wild-type and gatekeeper mutant FGFR4. These new derivatives showed significant FGFR4 inhibitory and antitumor activities, among which compound 27i was demonstrated to be the most potent compound (FGFR4 IC50 = 2.4 nM). Remarkably, compound 27i exhibited no activity against a panel of 381 kinases at 1 µM. Additionally, compound 27i displayed nanomolar IC50s against huh7 (IC50 = 21 nM) and two mutant cell lines, BaF3/ETV6-FGFR4-V550L and BaF3/ETV6-FGFR4-N535K (IC50 = 2.5/171 nM). Meanwhile, compound 27i exhibited potent antitumor potency (TGI: 83.0%, 40 mg/kg, BID) in Huh7 xenograft mouse models with no obvious toxicity observed. Overall, compound 27i was identified as a promising preclinical candidate for overcoming FGFR4 gatekeeper mutations for HCC treatment.

Effects of miR-145 targeting rab5c and regulating MAPK / ERK signaling pathway on proliferation and invasion of thyroid papillary carcinoma cells.

The objective of this research was to analyze the miR-145 function in thyroid papillary carcinoma cells and explore its possible mechanism. For this purpose, the TPC-1 cell line was selected, miR-145 overexpression and rab5c shRNA lentiviral vector were constructed, and transfected into PTC cells. Luciferase reporter gene was performed to determine the relationship between miR-145 and rab5c, Western blot and qPCR were performed to detach the expression of the related genes, CCK-8 cell proliferation assay and Transwell cell invasion assay were used to determine the proliferation and invasion ability of PTC-1 cells. Results showed that MiR-145 overexpression inhibited the wt-rab5c (wild-type rab5c)luciferase activity, decreased the expression of rab5c mRNA and protein levels in the TPC-1 cell line, inhibited the proliferation and invasion of PTC cell line TPC-1(P < 0.05). In TPC-1 cells, both miR-145 overexpression and RNA interference with rab5c could increase the expression of the p-ERK protein (P < 0.05). In conclusion, MiR-145 inhibits the proliferation and invasion of PTC cells by downregulating rab5c and activating MAPK/ERK pathway in vitro.

Effect of Cold-Water Irrigation on the Coblation Site for Post-Tonsillectomy Pain: A Prospective Randomized Clinical Study.

OBJECTIVE: To explore the effect of cold-water irrigation on post-tonsillectomy pain after coblation. METHODS: Data from 61 adult patients who underwent coblation tonsillectomy in our hospital from January 2019 to December 2020 were collected, and the patients were randomly divided into the cold-water irrigation group (Group 1) and the room-temperature irrigation group (Group 2). Group 1 was irrigated with ice water mixed saline with the help of a pressure band, and Group 2 was irrigated with room-temperature saline. During the operation, we monitored the temperature of the operating cavity in real time. We recorded the postoperative pain for 11 consecutive days from the day and the 10th day after the operation. RESULTS: The postoperative pain score was significantly lower than that in Group 2, except on the 2nd, 3rd and 7th and 8th days after the operation. CONCLUSION: The perfusion of cold water during coblation tonsillectomy is helpful to reduce postoperative pain.

Lactobacillus paracasei TK1501 fermented soybeans alleviate dextran sulfate sodium-induced colitis by regulating intestinal cell function.

BACKGROUND: Probiotic food provide health benefits by regulating intestinal floras via live bacteria, but the shelf life is short and the preservation condition is demanding due to the bacteria being fragile. Owing to these problems, we have tried to find a fermented food that is helpful for inflammatory bowel disease treatment but independent of live bacteria. In addition, the mechanisms of fermented food were investigated. Dextran sulfate sodium was used to model inflammatory bowel disease in mice, and Lactobacillus paracasei TK1501 fermented soybeans and their metabolites were used to treat inflammatory bowel disease. RESULTS: In this study, TK1501 fermented soybean alleviated colitis. However, the efficacy was associated with bacterial metabolites but not live or dead bacteria. Compositional analysis of soybean before and after fermentation shows that soy carbohydrates were used for bacteria growth and produced functional substances. Further, we display the main active ingredient was lipoteichoic acid and peptidoglycan, because lipoteichoic acid reduced the colonic macrophage and peptidoglycan may increase the mucin-2 expression. A cell experiment displayed that lipoteichoic acid could enhance the phagocytosis of macrophages. CONCLUSION: In general, TK1501 fermented soybean alleviating colitis is dependent on metabolites of TK1501, particularly lipoteichoic acid and peptidoglycan. The fermented food may have a long shelf life and lax storage condition. © 2023 Society of Chemical Industry.

[Study on the sensitivity of a volumetric modulated arc therapy plan verification equipment on multi-leaf collimator opening and closing errors and its gamma pass rate limit].

To investigate the γ pass rate limit of plan verification equipment for volumetric modulated arc therapy (VMAT) plan verification and its sensitivity on the opening and closing errors of multi-leaf collimator (MLC), 50 cases of nasopharyngeal carcinoma VMAT plan with clockwise and counterclockwise full arcs were randomly selected. Eight kinds of MLC opening and closing errors were introduced in 10 cases of them, and 80 plans with errors were generated. Firstly, the plan verification was conducted in the form of field-by-field measurement and true composite measurement. The γ analysis with the criteria of 3% dose difference, distance to agreement of 2 mm, 10% dose threshold, and absolute dose global normalized conditions were performed for these fields. Then gradient analysis was used to investigate the sensitivity of field-by-field measurement and true composite measurement on MLC opening and closing errors, and the receiver operating characteristic curve (ROC) was used to investigate the optimal threshold of γ pass rate for identifying errors. Tolerance limits and action limits for γ pass rates were calculated using statistical process control (SPC) method for another 40 cases. The error identification ability using the tolerance limit calculated by SPC method and the universal tolerance limit (95%) were compared with using the optimal threshold of ROC. The results show that for the true composite measurement, the clockwise arc and the counterclockwise arc, the descent gradients of the γ passing rate with per millimeter MLC opening error are 10.61%, 7.62% and 6.66%, respectively, and the descent gradients with per millimeter MLC closing error are 9.75%, 7.36% and 6.37%, respectively. The optimal thresholds obtained by the ROC method are 99.35%, 97.95% and 98.25%, respectively, and the tolerance limits obtained by the SPC method are 98.98%, 97.74% and 98.62%, respectively. The tolerance limit calculated by SPC method is close to the optimal threshold of ROC, both of which could identify all errors of ±2 mm, while the universal tolerance limit can only partially identify them, indicating that the universal tolerance limit is not sensitive on some large errors. Therefore, considering the factors such as ease of use and accuracy, it is suggested to use the true composite measurement in clinical practice, and to formulate tolerance limits and action limits suitable for the actual process of the institution based on the SPC method. In conclusion, it is expected that the results of this study can provide some references for institutions to optimize the radiotherapy plan verification process, set appropriate pass rate limit, and promote the standardization of plan verification.

Design, synthesis and biological evaluation of novel 9-methyl-9H-purine and thieno[3, 2-d]pyrimidine derivatives as potent mTOR inhibitors.

The mammalian target of rapamycin (mTOR) has been proved to be an effective target for cancer therapy. Two kinds of mTOR inhibitors, the rapalogs and mTOR kinase inhibitors (TORKi), have been developed and clinically validated in several types of malignancies. Compared with rapalogs, TORKi can exert better antitumor activity by inhibiting both mTORC1 and mTORC2, but the clinical development of current TORKi candidates has been relative slow, more TORKi with novel scaffold need to be developed to expand the current pipelines. In this study, a series of 9-methyl-9H-purine and thieno[3, 2-d]pyrimidine derivatives were designed, synthesized and biological evaluation. Most of these compounds exhibited good mTOR kinase inhibitory activity and selectivity over PI3Kα. Subsequent antiproliferative assay allowed us to identify the lead compound 15i, which display nanomolar to low micromolar IC50s against six human cancer cell lines. 15i could induce cell cycle arrest of MCF-7, PC-3 and A549 cells at the G0/G1 phase and suppress the migration and invasion of these cancer cells by suppressing the phosphorylation of AKT and P70S6 kinase. It could also regulate autophagy-related proteins to induce autophagy. Therefore, 15i would be a starting point for the development of new TORKi as anticancer drug.

Discovery of a Novel Covalent EZH2 Inhibitor Based on Tazemetostat Scaffold for the Treatment of Ovarian Cancer.

Enhancer of zeste homologue 2 (EZH2) is the enzymatic catalytic subunit of polycomb repressive complex 2 (PRC2), which plays an important role in post-translational modifications of histones. In this study, we designed and synthesized a new series EZH2 covalent inhibitors that have rarely been reported. Biochemical studies and mass spectrometry provide information that SKLB-03220 could covalently bind to the S-adenosylmethionine (SAM) pocket of EZH2. Besides, SKLB-03220 was highly potent for EZH2MUT, while exhibiting weak activities against other tested histone methyltransferases (HMTs) and kinases. Moreover, SKLB-03220 displayed noteworthy potency against ovarian cancer cell lines and continuously abolished H3K27me3 after washing out. Furthermore, oral administration of SKLB-03220 significantly inhibited tumor growth in PA-1 xenograft model without obvious adverse effects. Taken together, SKLB-03220 is a potent, selective EZH2 covalent inhibitor with noteworthy anticancer efficacy both in vitro and in vivo.

Left frontal eye field encodes sound locations during passive listening.

Previous studies reported that auditory cortices (AC) were mostly activated by sounds coming from the contralateral hemifield. As a result, sound locations could be encoded by integrating opposite activations from both sides of AC ("opponent hemifield coding"). However, human auditory "where" pathway also includes a series of parietal and prefrontal regions. It was unknown how sound locations were represented in those high-level regions during passive listening. Here, we investigated the neural representation of sound locations in high-level regions by voxel-level tuning analysis, regions-of-interest-level (ROI-level) laterality analysis, and ROI-level multivariate pattern analysis. Functional magnetic resonance imaging data were collected while participants listened passively to sounds from various horizontal locations. We found that opponent hemifield coding of sound locations not only existed in AC, but also spanned over intraparietal sulcus, superior parietal lobule, and frontal eye field (FEF). Furthermore, multivariate pattern representation of sound locations in both hemifields could be observed in left AC, right AC, and left FEF. Overall, our results demonstrate that left FEF, a high-level region along the auditory "where" pathway, encodes sound locations during passive listening in two ways: a univariate opponent hemifield activation representation and a multivariate full-field activation pattern representation.

Brain-wide inputs to the non-lemniscal inferior colliculus in mice.

The inferior colliculus (IC) is the hub along the auditory pathway. Although it is fundamentally an auditory structure, the neurons in the IC, especially its non-lemniscal part also respond to multimodal stimuli. However, the sources of these non-auditory inputs are unclear. In this study, we injected the rAAV2-retro virus, a virus with efficient retrograde function, into the non-lemniscal IC of the Ai14 reporter line. The majority of cortical and subcortical brain areas, including cognitive, motor, somatosensory, auditory, and visual-related regions were revealed. The quantified whole brain input data have showed that the non-lemniscal IC received a higher proportion of inputs from ipsilateral cortical brain regions. The non-lemniscal IC integrates different multimodal patterns, for the dorsal cortex (ICD) receives primarily auditory inputs, and the external cortex (ICE) receives primarily auditory and somatosensory inputs. These findings demonstrate that auditory integration is shaped by a network of multi-sensory connections in the non-lemniscal IC subregions.

Case Report: A novel mixture of dose-fractioned radiation and immunotherapy for treatment of cholangiocarcinoma.

Malignant tumors of the biliary tract exhibit a high degree of malignancy and heterogeneity with a poor overall prognosis. Immunotherapy has limited benefits for patients with cholangiocarcinoma. Radiation therapy can change the tumor microenvironment, but its effect heavily depends on radiation dose and fraction. We report a case of advanced intrahepatic cholangiocarcinoma in a 43-year-old male patient, with a huge liver mass of 16.5 cm in diameter, with bone and liver metastases at the first diagnosis. First-line treatment with chemotherapy and PD1 inhibitor was sustained only for 8 months. In second-line treatment, radiotherapy was administered, with 5 Gy in 5 fractions administered to the entire tumor area and 25 Gy in 5 fractions to the solid lesions of the tumor. After the completion of radiotherapy, programmed cell death 1 inhibitor combined with tyrosine kinase inhibitor was maintained. The patient achieved a progression-free-survival time of 12 months and an overall survival time of 25 months. The success of our case suggests that mixed low- and high-dose radiation can significantly improve tumor control and survival time. In clinical practice, based on the characteristics of the tumor and existing treatment options, the rational combination of existing treatment regimens can improve the prognosis of cholangiocarcinoma.